Dr. Agarwala and I continue collaborations with L. Biesecker (NHGRI) and the group of A.Shuldiner and B. Mitchell (U. Maryland Medical School) in development and usages of the Anabaptist Genealogy Database (AGDB), a large computer-searchable genealogy of North American Anabaptists, which was constructed in previous years. The main advance during the past year was that Dr. Agarwala, summer student Joshua Rosenthal, and I enlarged the database from over 295,000 individuals (version 3, finished in 2000) to over 417,000 individuals (now called AGDB, version 4). We also added several new queries and other features to our PedHunter software that is used by us to search AGDB and by other groups to search their own genealogy databases. Drs. Agarwala, Biesecker and I continued a collaboration with D. Marchuk (Duke University) hunting for one or more genes associated with venous malformations in the Amish. During this past year the collaboration with Drs. Shuldiner and Mitchell yielded one manuscript on incidence of hip fractures and osteoporosis published in Journal of Bone and Mineral Research. I continue to collaborate with Dr. B. Grimbacher (U. Freiburg) and Dr. J. Puck (NHGRI) to hunt genes for hyperIgE syndrome, common variable immune deficiency (CVID), neutropenia, and other disorders related to the immune system. During the past 12 months: Dr. Grimbacher and I published one reviewe article on common variable immune deficiency Dr. Grimbacher identified strong evidence for a gene causing neutropenia, based on a list of candidate genes I derived last year; Dr. Grimbacher identified mutations in two new candidate genes for common variable immune deficiency, in some families we are also studying by linkage analysis; In those same families I reanalyzed previously published genotype data in a new way, and identified 3 genomic regions worthy of fine fine mapping and further analysis. Dr. Puck and I studied analyzed some genes that are good candidates to modify the severity of the ALPS phenotype. My collaboration with Dr. S. Holland (NIAID) on studies to characterize polymorphisms and haplotypes in two human genes of interest in host defense against infection yielded two published papers: one on promoter polymorphisms of the INFNGR1 gene and the other on an intronic polymorphism of the TLR2 gene. I continue to collaborate with P. Henthorn (U. Penn) and J. Fyfe (Michigan State) on a linkage study of a large canine pedigree that has multiple occurrences of three autosomal recessive traits. During the past 12 months a paper on linkage for a vitamin B12 malabsorption trait was published for publication in Mammalian Genome. We continued to hunt genes for the other two traits, but have not found linkage yet. My collaboration with Dr. Fyfe was expanded and coalesced with the cat map work described below to also include genetic studies of a cat pedigree with numerous cases of spinal muscular atrophy, not caused by disruptions of the SMN gene (which is the principal cause of spinal muscular atrophy in humans). Dr. Agarwala I continue to collaborate with M. Mennoti-Raymond(NCI) and W. J. Murphy (was at NC, moved to Texas A&M) on construction of maps for use in genetics. In the past 12 months we: published a third-generation radiation hybrid map of the cat in Cytogenetic and Genome Research, completed computation of a first radiation hybrid map of the macaque made numerous improvements to our rh_tsp_map software, which is used both by us in these projects and independently by other groups computing radiation hybrid maps. Dr. Richard Desper and I completed our collaboration with with Z. Huang and K. Yao (Guangzhou, China) on a study of comparative genomic hybridization data from nasopharygeal cancer. We revised a manuscript summarizing our findings, and it was published in Genes, Chromosomes & Cancer. Dr. Desper and I continued collaborating with Dr. Javed Khan (NICHD) on a new method of tumor classificaation from microarray data. During the past 12 months we refined the method and revised a manuscript describing the method and published it in Journal of Theoretical Biology. Dr. Desper and I collaborated with the group of Dr. Thomas Ried (NCI) on two problems in modeling aneuploidy in cancer cells. For a problem concerning modeling of possible mitotic advantage conferred by a genomic mutation, we completed both analytic work leading to closed-fom solutions as well as a simulation program. We wrote a manuscript on the mitotis modeling problem and submitted it for publication. Dr. Robert Nussbaum (NHGRI) invited me to resume our collaboration on hunting genes for Parkinson's disease, now joined by Dr. Andrew Singleton (NINDS). I had done the genetic linkage analysis computations for the first two Parkinson's disease loci in 1996. During the past year, I analyzed genome scan genotype data for two new large Parkinson's pedigrees. One pedigree shows dominant inheritance, and the other pedigree probably has recessive inheritance. In each case, we have identified at least one genomic region that looks very promising, and fine mapping of those regions is underway.